The prospect of gene therapy gives a new perspective to medicine, allowing a revolutionary approach to treat diseases at the level where they are generated, namely the living cell. When the cellular machinery is impaired due to a deficient gene, a functional gene incorporated into an appropriate vector may be delivered to the affected cells, tissues or organs. After internalization, the DNA is transferred to the nucleus where the gene is integrated into the host genome, transcribed and finally translated into the proteins needed to correct the cellular imbalance. Despite the simple concept, the eventual success of this new form of therapy relies on the efficiency of the overall delivery process.
Viral vectors are currently the most efficient systems for the transfer and expression (transfection) of foreign DNA into living cells. However, their effectiveness is hampered by serious side effects, such as immunogenicity, difficulties associated with good manufacturing practice (GMP) production or storage, a limited size of the DNA that can be inserted into the virion, mutagenicity, and sometimes fatal toxicity.
Cationic lipids have emerged as safer alternatives to viral delivery. Having low immunogenicity and cytotoxicity, they also allow the use of plasmids of practically unlimited size and can be easily manufactured and stored in bulk quantities under GMP-compliant norms. In order to bind and compact DNA efficiently, the cationic lipids usually must self-assemble first into cationic liposomes. Under this form they interact with the negatively charged plasmids to yield cationic lipids-DNA complexes (lipoplexes) with differing sizes and shapes. The characteristics of the lipoplexes are essential for their efficiency. Variables such as the lipid nature and composition of the parent cationic liposomes, the characteristics of the plasmid or the method used to generate the lipoplexes are critical for achieving high levels of transfection.
Despite tremendous synthetic efforts that have generated several commercial cationic lipid transfection systems (DOTMA—Di-C14-amidine), there is still a need for improving in vivo efficiency and decreasing cytotoxicity. In this context, the heterocyclic cationic lipids newly introduced by several different groups represent a promising alternative, displaying higher transfection efficiencies and a reduced cytotoxity when compared with their tetraalkylammonium congeners.